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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®)

Anal Carcinoma

Version 1.2016

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NCCN Guidelines Index

Anal Carcinoma Table of Contents

Discussion


NCCN Guidelines Version 1.2016 Panel Members

Anal Carcinoma

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NCCN Guidelines Panel Disclosures

† Medical oncology§ Radiotherapy/Radiation

oncology¶ Surgery/Surgical oncology

≠ Pathology‡ Hematology/Hematology oncology

Þ Internal medicineф Diagnostic/Interventional

radiology¤ Gastroenterology

¥ Patient advocate*Discussion Section WritingCommittee

NCCNDeborah Freedman-Cass, PhDKristina M. Gregory, RN, MSN, OCN

Al B. Benson, III, MD/Chair †Robert H. Lurie Comprehensive CancerCenter of Northwestern University

Alan P. Venook, MD/Vice-Chair † ‡

UCSF Helen Diller FamilyComprehensive Cancer Center

Tanios Bekaii-Saab, MD †The Ohio State University ComprehensiveCancer Center - James Cancer Hospitaland Solove Research Institute

Emily Chan, MD, PhD †Vanderbilt-Ingram Cancer Center

Yi-Jen Chen, MD, PhD §City of Hope ComprehensiveCancer Center

Harry S. Cooper, MD ≠

Fox Chase Cancer Center

Paul F. Engstrom, MD †Fox Chase Cancer Center

Peter C. Enzinger, MD †Dana-Farber/Brigham and Women’sCancer Center

Moon J. Fenton, MD, PhD †St. Jude Children’s Research Hospital/University of Tenessee Health ScienceCenter

Charles S. Fuchs, MD, MPH †Dana-Farber/Brigham and Women’sCancer Center

Jean L. Grem, MD †Fred & Pamela Buffett Cancer Center

*

*

Axel Grothey, MD †Mayo Clinic Cancer Center

Howard S. Hochster, MD Yale Cancer Center/Smilow Cancer Hospital

Steven Hunt, MD ¶Siteman Cancer Center at Barnes-Jewish Hospital and WashingtonUniversity School of Medicine

Ahmed Kamel, MD фUniversity of Alabama at BirminghamComprehensive Cancer Center

Natalie Kirilcuk, MD ¶Stanford Cancer Institute

Smitha Krishnamurthi, MD † ÞCase Comprehensive Cancer Center/University Hospitals SeidmanCancer Center and ClevelandClinic Taussig Cancer Institute

Lucille A. Leong, MD †City of Hope ComprehensiveCancer Center

Edward Lin, MD †Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance

Wells A. Messersmith, MD †University of Colorado Cancer Center

Mary F. Mulcahy, MD ‡ †Robert H. Lurie Comprehensive CancerCenter of Northwestern University

James D. Murphy, MD, MS §UC San Diego Moores Cancer Center

Steven Nurkin, MD, MS ¶Roswell Park Cancer Institute

David P. Ryan, MD †Massachusetts General HospitalCancer Center

Leonard Saltz, MD † ‡ ÞMemorial Sloan Kettering Cancer Center

Sunil Sharma, MD †Huntsman Cancer Instituteat the University of Utah

John M. Skibber, MD ¶The University of TexasMD Anderson Cancer Center

Constantinos T. Sofocleous, MD, PhD фMemorial Sloan Kettering Cancer Center

Elena M. Stoffel, MD, MPH ¤ University of MichiganComprehensive Cancer Center

Eden Stotsky-Himelfarb, BSN, RN ¥The Sidney Kimmel ComprehensiveCancer Center at Johns Hopkins

Christopher G. Willett, MD §Duke Cancer Institute

*

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http://www.nccn.org/disclosures/panel_list.asp?ID=28




Clinical Trials: NCCN believes that

the best management for any cancerpatient is in a clinical trial.Participation in clinical trials isespecially encouraged.

To nd clinical trials online at NCCNMember Institutions, click here:nccn.org/clinical_trials/physician.html.

NCCN Categories of Evidence andConsensus: All recommendationsare category 2A unless otherwise

specied.See NCCN Categories of Evidenceand Consensus.

NCCN Anal Carcinoma Panel Members

Summary of the Guidelines Updates

Workup and Treatment - Anal Canal Cancer (ANAL-1)

Workup and Treatment - Anal Margin Lesion (ANAL-2)

Follow-up Therapy and Surveillance (ANAL-3)

Principles of Chemotherapy (ANAL-A)

Principles of Radiation Therapy (ANAL-B)

Staging (ST-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.

Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical

circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or

warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN

Guidelines are copyrighted by National Comprehensive Cancer Network®

. All rights reserved. The NCCN Guidelines and the illustrations herein may notbe reproduced in any form without the express written permission of NCCN. ©2015.


NCCN Guidelines Version 1.2016 Table of Contents

Anal Carcinoma



Discussion


http://www.nccn.org/clinical_trials/clinicians.aspx










Discussion

Version 1.2016, 11/04/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN ®. UPDATES

NCCN Guidelines Version 1.2016 Updates

Anal Carcinoma

Updates in Version 1.2016 of the NCCN Guidelines for Anal Carcinoma from Version 2.2015 include:

ANAL-1

• Workup; bullet 2, sub-bullet 1 modied: “Consider biopsy or FNA if suspicious nodes.”

• Workup; bullet 3 modied: “Chest/abdominal/pelvic CT or + pelvic CT or MRI”

• Workup; bullet 3, sub-bullet 1 modied: “Consider PET scan for T2-4, N0 or Any T, N+”

• Footnote “c” added: “CT should be with IV and oral contrast. Pelvic MRI with contrast.” (also applies to ANAL-2)

• Clinical Stage: T and N categories combined to “locoregional” disease.

ANAL-2

• Workup; bullet 2, sub-bullet 1 modied: “Consider biopsy or FNA if suspicious nodes.”

• Workup; bullet 3 modied: “Chest/abdominal/pelvic CT or + pelvic CT or MRI”

• Workup; bullet 3, sub-bullet 1 modied: “Consider PET scan for T2-4, N0 or Any T, N+”

ANAL-3

• Surveillance: Anoscopy schedule changed from every 3–6 mo for 5 y to every 6–12 mo x 3 y

ANAL-B• Bullet 6 modied: “For T2 lesions with residual disease after 45 Gy, T3/4 lesions, or N1 lesions, an additional boost of 9–14 Gy in 1.8–2 Gy

fractions to the original primary tumor volume and involved nodes plus a 2–2.5 cm margin is usually delivered.”

• Bullet 7 modied: “The consensus of the panel is that intensity-modulated radiation therapy (IMRT) may be used in place of is preferred over

3-D conformal RT in the treatment of anal carcinoma. IMRT requires expertise and careful target design to avoid reduction in local control by

so-called ‘marginal-miss.’ The clinical target volumes for anal cancer used in the RTOG-0529 trial have been described in detail. The outcome

results of RTOG-0529 have been reported.”

• Reference added: “Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation

therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat

Oncol Biol Phys 2013;86:27-33.”


P i t d b J i B tid 2/25/2016 3 41 00 AM F l l N t d f di t ib ti C i ht © 2016 N ti l C h i C N t k I All Ri ht R d





NCCN Guidelines Version 1.2016

Anal Carcinoma


Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.



Discussion

• Digital rectal examination (DRE)

• Inguinal lymph node evaluation

Consider biopsy or FNA if

suspicious nodes

• Chest/abdominal CTc + pelvic

CT or MRI

Consider PET scand

• Anoscopy

• Consider HIV testing + CD4 levelif indicated

• Gynecologic exam for women,

including screening for cervical

cancer

ANAL-1

aThe superior border of the functional anal canal, separating it from the rectum, has been defined as the palpable upper border of the anal sphincter and puborectalismuscles of the anorectal ring. It is approximately 3 to 5 cm in length, and its inferior border starts at the anal verge, the lowermost edge of the sphincter muscles,corresponding to the introitus of the anal orifice.

bFor melanoma histology, see the NCCN Guidelines for Melanoma; for adenocarcinoma, see the NCCN Guidelines for Rectal Cancer .cCT should be with IV and oral contrast. Pelvic MRI with contrast.dPET-CT scan does not replace a diagnostic CT. The routine use of a PET-CT scan for staging or treatment planning has not been validated.ePatients with anal cancer as the first manifestation of HIV may be treated with the same regimen as non-HIV patients. Patients with active HIV/AIDS-related

complications or a history of complications (eg, malignancies, opportunistic infections) may not tolerate full-dose therapy or may not tolerate mitomycin and requiredosage adjustment or treatment without mitomycin.

f See Principles of Chemotherapy (ANAL-A).gSee Principles of Radiation Therapy (ANAL-B).hCisplatin/5-FU is recommended for metastatic disease. If this regimen fails, no other regimens have been shown to be effective.

See Principles of Chemotherapy (ANAL-A). Local control can be achieved with the use of RT.

CLINICAL

PRESENTATION

WORKUP CLINICAL STAGE PRIMARY TREATMENTe

Anal canal

cancer a

Biopsy:

squamous

cell

carcinoma

b

Metastatic

disease

Mitomycin/5-FUf + RTg

or

Mitomycin/

Capecitabinef + RTg

Cisplatin-based

chemotherapyh ± RTg

See Follow-up

Therapy and

Surveillance

(ANAL-3)

Locoregional

disease


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http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf

http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf







Anal Carcinoma





Discussion

• DRE

• Inguinal lymph node

evaluation

Consider biopsy or FNA if

suspicious nodes

• Chest/abdominal CTc +

pelvic CT or MRI

Consider PET scand

• Anoscopy• Consider HIV testing + CD4

level if indicated

• Gynecologic exam for

women, including screening

for cervical cancer

ANAL-2

bFor melanoma histology, see the NCCN Guidelines for Melanoma; for adenocarcinoma, see the NCCN Guidelines for Rectal Cancer .cCT should be with IV and oral contrast. Pelvic MRI with contrast.dPET-CT scan does not replace a diagnostic CT. The routine use of a PET-CT scan for staging or treatment planning has not been validated.ePatients with anal cancer as the first manifestation of HIV may be treated with the same regimen as non-HIV patients. Patients with active HIV/AIDS-related

complications or a history of complications (eg, malignancies, opportunistic infections) may not tolerate full-dose therapy or may not tolerate mitomycin and requiredosage adjustment or treatment without mitomycin.

f See Principles of Chemotherapy (ANAL-A).gSee Principles of Radiation Therapy (ANAL-B).hCisplatin/5-FU is recommended for metastatic disease. If this regimen fails, no other regimens have been shown to be effective.

See Principles of Chemotherapy (ANAL-A). Local control can be achieved with the use of RT.iThe anal margin starts at the anal verge and includes the perianal skin over a 5- to 6-cm radius from the squamous mucocutaneous junction.

CLINICAL

PRESENTATIONWORKUP CLINICAL STAGE PRIMARY TREATMENTe

Anal

margin

lesioni

Biopsy:

squamous

cell

carcinomab

T1, N0Well

differentiated

T2-T4, N0 or

Any T, N+

Metastatic

disease

Local

excision

Adequate

marginsObserve

Inadequate

margins

Re-excision(preferred)or Consider local RTg ± 5-FU orcapecitabine-basedchemotherapyf

See Follow-up

Therapy and

Surveillance

(ANAL-3)

See Follow-up

Therapy and

Surveillance(ANAL-3)

Cisplatin-based chemotherapyh ± RTg

Mitomycin/5-FUf + RTg

or

Mitomycin/Capecitabinef + RTg












Anal Carcinoma



Discussion



ANAL-3

gSee Principles of Radiation Therapy (ANAL-B).hCisplatin/5-FU is recommended for metastatic disease. If this regimen fails, no other regimens have been shown to be effective.

See Principles of Chemotherapy ANAL-A. Local control can be achieved with the use of RT. jIf a patient with an initially tethered tumor returns 6 weeks post RT with a mobile but suspicious mass, consider biopsy.kBased on the results of the ACT-II study, it may be appropriate to follow patients who have not achieved a complete clinical response with persistent anal cancer up to 6 months following

completion of radiation therapy and chemotherapy as long as there is no evidence of progressive disease during this period of follow-up. Persistent disease may continue to regress evenat 26 weeks post-treatment. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamouscell carcinoma of the anus (Act II): a randomised, phase 3, open-label, 2x2 factorial trial. Lancet Oncol 2013;14:516-524.

lConsider muscle flap reconstruction.mThere is no evidence supporting resection of metastatic disease.

FOLLOW-UP TREATMENT SURVEILLANCE

Evaluate in 8–12

weeks j with

exam + DRE

Progressive

diseasek

Persistent

diseasek

Complete

remission

Biopsy

provenRestage

Locally

recurrent

Metastatic

disease

Abdominoperineal

resection (APR)l

5-FU/Cisplating

• Inguinal node palpation

every 3–6 mo for 5 y

• Chest/abd/pelvicimaging annually x 3 y

Re-evaluate

in 4 wks

• DRE every 3–6 mo for 5 y• Inguinal node palpation

every 3–6 mo for 5 y• Anoscopy every 6–12 mo

x 3 y• Chest/abd/pelvic imaging

annually for 3 y (if T3-T4

or inguinal node positive)

Progression on

serial exams

No progression

or regression on

serial exams

If progression

Continue

observation and

re-evaluate in 3 mo

Local

recurrence

Inguinal node

recurrence

Distant

metastasism

APRl + groin dissection,

if positive inguinal nodes

• Groin dissection

• Consider RT,g if no prior RT

to groin ± chemotherapy

Cisplatin-based chemotherapyh

orClinical trial

• DRE every 3–6 mo for 5 y• Inguinal node palpation

every 3–6 mo for 5 y• Anoscopy every 6-12 mo

x 3 y• Chest/abd/pelvic imaging

annually for 3 y

ted by Ju o ast das o / 5/ 0 6 3 00 o pe so a use o y ot app o ed o d st but o Copy g t © 0 6 at o a Co p e e s e Ca ce et o , c , g ts ese ed







Anal Carcinoma



Discussion


Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Localized cancer

5-FU + Mitomycin + RT1

Continuous infusion 5-FU 1000 mg/m2 /d IV days 1–4 and 29–32

Mitomycin 10 mg/m2 IV bolus days 1 and 29

Concurrent radiotherapy (See ANAL-B)

Capecitabine + Mitomycin + RT2,3

• Capecitabine 825 mg/m2 PO BID, Monday–Friday,

on each day that RT is given, throughout the duration of RT

(typically 28 treatment days)

Mitomycin 10 mg/m2 days 1 and 29


or

• Capecitabine 825 mg/m2 PO BID days 1–5 weekly x 6 weeks

Mitomycin 12 mg/m2 IV bolus day 1


Metastatic cancer

5-FU + Cisplatin4

Continuous infusion 5-FU 1000 mg/m2 /d IV days 1–5

Cisplatin 100 mg/m2 IV day 2

Repeat every 4 weeks

ANAL-A

1 Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: arandomized controlled trial. JAMA 2008;299:1914-1921.

2Goodman KA, Rothenstein D, Cambridge L, et al. Capecitabine plus mitomycin in patients undergoing definitive chemoradiation for anal squamous cell carcinoma. Int JRadiat Oncol Biol Phys 2014 (in press).

3Thind G, Johal B, Follwell M, & Kennecke HF. Chemoradiation with capecitabine and mitomycin-C for stage I-III anal squamous cell carcinoma. Radiation Oncology2014;9:124.

4Faivre C, Rougier P, Ducreux M, et al. 5-fluorouracil and cisplatin combination chemotherapy for metastatic squamous-cell anal cancer. Bull Cancer 1999;86:861-5.

PRINCIPLES OF CHEMOTHERAPY







Anal Carcinoma



Discussion


Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

• Multield techniques with supervoltage radiation (photon energy of >6 mV) should be used to deliver a minimum dose of 45 Gy in 1.8 Gy-

fractions (25 fractions over 5 weeks) to the primary cancer.

• PET-CT should be considered for treatment planning.• The inguinal nodes and the pelvis, anus, and perineum should be included in the initial radiation elds. The superior eld border should

be at L5-S1, and the inferior border should include the anus with a minimum 2.5-cm margin around the anus and tumor. The lateral border

should include the lateral inguinal nodes (as determined from imaging or bony landmarks). There should be attempts to reduce the dose to

the femoral heads.

• After 17 fractions (30.6 Gy), an additional 14.4 Gy should be given in 8 fractions with the superior eld reduced to the bottom of the sacroiliac

joints. Additional eld reduction off inguinal nodes should occur after 36 Gy for node-negative lesions. This protocol brings the total dose to

45 Gy in 25 fractions over 5 weeks.

• For patients treated using an AP-PA technique, rather than the recommended multield technique, the dose to the lateral inguinal region

should be brought to the minimum dose of 36 Gy using an anterior electron boost matched to the PA exit eld.

• For T2 lesions, T3/4 lesions, or N1 lesions, an additional boost of 9–14 Gy in 1.8–2 Gy fractions to the original primary tumor volume and

involved nodes plus a 2–2.5 cm margin is usually delivered. This boost brings the total dose to 54–59 Gy in 30–32 fractions over 6–7.5weeks. A direct perineal boost using photons or electrons with the patient in lithotomy position or a multield photon approach (AP-PA plus

paired laterals, PA + laterals, or other) can be used.

• The consensus of the panel is that intensity-modulated radiation therapy (IMRT) is preferred over 3-D conformal RT in the treatment of anal

carcinoma.2 IMRT requires expertise and careful target design to avoid reduction in local control by so-called “marginal-miss.”3 The clinical

target volumes for anal cancer used in the RTOG-0529 trial have been described in detail.2 The outcome results of RTOG-0529 have been

reported.4

Also see http://atc.wustl.edu/protocols/rtog-closed/0529/ANAL_Ca_CTVs_5-21-07_Final.pdf for more details of the contouring atlas dened

by RTOG.

• Side effect management:

Female patients should be considered for vaginal dilators and instructed on the symptoms of vaginal stenosis.Male patients should be counseled on infertility risks and given information regarding sperm banking.

Female patients should be counseled on infertility risks and given information regarding oocyte, egg, or ovarian tissue banking prior to

treatment.

ANAL-B

1 Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. JAMA2008;299:1914-1921.

2Myerson RJ, Garofalo MC, El Naqa I, et al. Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensuspanel contouring atlas. Int J Radiat Oncol Biol Phys 2009;74:824-830.

3Pepek JM, Willett CG, Czito BG. Radiation therapy advances for treatment of anal cancer. J Natl Compr Canc Netw 2010;8:123-129.4Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and

mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:27-33.

PRINCIPLES OF RADIATION THERAPY1



http://atc.wustl.edu/protocols/rtog-closed/0529/ANAL_Ca_CTVs_5-21-07_Final.pdf

http://atc.wustl.edu/protocols/rtog-closed/0529/ANAL_Ca_CTVs_5-21-07_Final.pdf






Discussion


NCCN Guidelines Version 1.2016 Staging

Anal Carcinoma

ST-1

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCCCancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Media, LLC (SBM). (For complete information and data supporting the

staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of thisinformation herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.

Table 1. DEFINITIONS OF TNM Table 2. ANATOMIC STAGE/PROGNOSTIC GROUPS

Primary Tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor Tis Carcinoma in situ (Bowen’s disease, high-grade squamous

intraepithelial lesion (HSIL), anal intraepithelial neoplasia II–III

(AIN II–III)

T1 Tumor 2 cm or less in greatest dimension

T2 Tumor more than 2 cm but not more than 5 cm in greatest

dimension

T3 Tumor more than 5 cm in greatest dimension

T4 Tumor of any size invades adjacent organ(s), e.g., vagina,

urethra, bladder*

*Note: Direct invasion of the rectal wall, perirectal skin,

subcutaneous tissue, or the sphincter muscle(s) is not classied as

T4.

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in perirectal lymph node(s)

N2 Metastasis in unilateral internal iliac and/or inguinal lymph

node(s)

N3 Metastasis in perirectal and inguinal lymph nodes and/or

bilateral internal iliac and/or inguinal lymph nodes

Distant Metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

Stage T N M

0 Tis N0 M0

I

T1 N0 M0II T2 N0 M0

T3 N0 M0

IIIA T1 N1 M0

T2 N1 M0

T3 N1 M0

T4 N0 M0

IIIB T4 N1 M0

Any T N2 M0

Any T N3 M0

IV Any T Any N M1


http://www.springer.com/?SGWID=0-102-0-0-0

http://www.springer.com/?SGWID=0-102-0-0-0




http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2012/Anus_12protocol_3200.pdf





http://www.redjournal.org/article/S0360-3016(14)00792-5/fulltext





http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125084s242lbl.pdf



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